Fellowship Jack Keady: Investigation Into The Sex And Cell Specific Impacts Of Nicotine Withdrawal In The Murine Hippocampus

Grants and Contracts Details

Description

Project Summary/Abstract Over 30 million people in the United States are current smokers, and while there are FDA approved therapeutics for smoking cessation and the desire to quit amongst smoker only about 8% will be successful for at a 6-12 month follow up. Furthermore, women are less likely to quit smoking compared to men, highlighting the need for new personalized pharmacotherapies for smoking cessation. Nicotine withdrawal causes both cognitive deficits and affective dysfunction, which may contribute to the low precent of successful quit attempts. Given the hippocampus’ well-defined regio-specific role in both contextual memory and affective responding, dorsal and ventral hippocampus respectively, it is a promising target for mechanistic evaluation of both the cognitive and affective symptoms of nicotine withdrawal. Previous sequencing data from our lab found that chronic nicotine and withdrawal impact the expression of many phosphatases and regulators of phosphatases in the hippocampus. My preliminary data shows that acute nicotine increases memory consolidation in contextual fear conditioning in a sex-specific manner, but chronic nicotine has no impact. Therefore, we then investigated chronic nicotine’s impact on memory reconsolidation using contextual fear extinction, but chronic nicotine had no effects. The current proposal will test the hypothesis that withdrawal from chronic nicotine causes deficits in contextual fear extinction in both male and female mice, and the observed cognitive deficits, as well as the previously well-defined affective dysfunction reported during nicotine withdrawal, are mediated by aberrant phosphatases expression in the hippocampus. I speculate that systemic inhibition of phosphatases and regio- and cell-type specific knockdown of certain phosphatases will alleviate deficits in contextual fear conditioning caused by nicotine withdrawal. I will test this hypothesis by exposing male and female mice to chronic saline, nicotine, and withdrawal during contextual fear extinction and running hippocampal tissue through single-cell RNA sequencing for cell specific identification of aberrant phosphatase expression. I will use systemic administration of phosphatase inhibitors to query the phosphatase’s role in nicotine withdrawal endophenotypes and validate the phosphatase’s role within the hippocampus using CRE-dependent Cas9 knock-in mice for regio- and cell-specific knock down of the phosphatase. These proposed experiments will highlight phosphatases as valid drug development targets for personalized smoking cessation therapies in women and men to address both the cognitive deficits and affective dysfunction experienced during nicotine withdrawal.
StatusActive
Effective start/end date9/1/238/31/24

Funding

  • American Foundation for Pharmaceutical Education: $10,000.00

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